Preliminary studies conducted in mice indicate that methamphetamine potentiates the liver injury from two model hepatotoxic compounds, acetaminophen and carbon tetrachloride. This potentiation caused substantial liver injury to result from doses of these compounds that otherwise produced little or no measurable toxicity. The observation that this potentiation effect occurred with two compounds producing hepatotoxicity by different mechanisms suggests that the phenomenon may be relevant to a variety of hepatotoxic agents. Other preliminary studies with another stimulant sympathomimetic amine, phenylpropanolamine, indicate that this potentiation phenomenon may be due to alpha2-adrenergic receptor stimulation. Based on these preliminary observations, it is hypothesized that methamphetamine is capable of increasing the responsiveness of liver to chemical toxicity through alpha-adrenergic receptor stimulation. The interaction between methamphetamine and the model hepatotoxic agents acetaminophen and carbon tetrachloride will be characterized in mice, and the hypothesis of alpha-adrenoreceptor involvement will be tested. Dose and temporal relationships for the interaction will be defined, and the importance of route of administration and single versus multiple doses of methamphetamine determined. Using adrenoreceptor agonists and antagonists selective for specific receptor subtypes, the involvement of adrenoreceptors in methamphetamine potentiation of toxicity will be ascertained. An additional objective is the tentative location of the receptors (peripheral versus central sites). Mechanistic studies will address the possibilities that methamphetamine increases the concentrations of hepatotoxic agents in the liver, and/or increases their bioactivation to toxic, reactive intermediates. Doses of methamphetamine implicit in its abuse can be expected to produce profound pharmacologic effects, perhaps including this effect on the liver. The implication of a methamphetamine shift in the dose-response relationships for hepatotoxicity is that exposure to ordinarily safe or borderline doses of a number of drugs and chemicals found in the home and workplace may result in liver injury, contributing to the morbidity and mortality associated with methamphetamine abuse.